This invention relates to methodologies and techniques which utilize programmable functionalized self-assembling nucleic acids, nucleic acid modified structures, and other selective affinity or binding moieties as building blocks for: (1) creating molecular electronic and photonic mechanisms; (2) for the organization, assembly, and interconnection of nanostructures, submicron and micron sized components onto silicon or other materials; (3) for the organization, assembly, and interconnection of nanostructures, submicron and micron sized components within perimeters of microelectronic or optoelectronic components and devices; (4) for creating, arraying, and manufacturing photonic and electronic structures, devices, and systems; (5) for the development of a high bit density (large byte) three and four dimensional optical data storage materials and devices; and (6) for development of low density optical memory for applications in authentication, anti-counterfeiting, and encryption of information in document or goods. This invention also relates to associated microelectronic and optoelectronic devices, systems, and manufacturing platforms which provide electric field transport and selective addressing of self-assembling, nanostructures, sub-micron and micron sized components to selected locations on the device itself or onto other substrate materials.
The fields of molecular electronics/photonics and nanotechnology offer immense technological promise for the future. Nanotechnology is defined as a projected technology based on a generalized ability to build objects to complex atomic specifications. Drexler, Proc. Natl. Acad. Sci USA, 78:5275-5278, (1981). Nanotechnology generally means an atom-by-atom or molecule-by-molecule control for organizing and building complex structures all the way to the macroscopic level. Nanotechnology is a bottom-up approach, in contrast to a top-down strategy like present lithographic techniques used in the semiconductor and integrated circuit industries. The success of nanotechnology may be based on the development of programmable self-assembling molecular units and molecular level machine tools, so-called assemblers, which will enable the construction of a wide range of molecular structures and devices. Drexler, xe2x80x9cEngines of Creation,xe2x80x9d Doubleday Publishing Co., New York, N.Y. (1986). Present molecular electronic/photonic technology includes numerous efforts from diverse fields of scientists and engineers. Carter, ed., xe2x80x9cMolecular Electronic Devices II,xe2x80x9d Marcel Dekker, Inc, New York, N.Y. (1987). Those fields include organic polymer based rectifiers, Metzger et al., xe2x80x9cMolecular Electronic Devices II,xe2x80x9d Carter, ed., Marcel Dekker, New York, N.Y., pp. 5-25 (1987), conducting conjugated polymers, MacDiarmid et al., Synthetic Metals, 18:285 (1987), electronic properties of organic thin films or Langmuir-Blogett films, Watanabe et al., Synthetic Metals, 28:C473 (1989), molecular shift registers based on electron transfer, Hopfield et al., Science, 241:817 (1988), and a self-assembly system based on synthetically modified lipids which form a variety of different xe2x80x9ctubularxe2x80x9d microstructures. Singh et al., xe2x80x9cApplied Bioactive Polymeric Materials,xe2x80x9d Plenum Press, New York, N.Y., pp. 239-249 (1988). Molecular optical or photonic devices based on conjugated organic polymers, Baker et al., Synthetic Metals, 28:D639 (1989), and nonlinear organic materials have also been described. Potember et al., Proc. Annual Conf. IEEE in Medicine and Biology, Part 4/6:1302-1303 (1989).
However, none of the cited references describe a sophisticated or programmable level of self-organization or self-assembly. Typically the actual molecular component which carries out the electronic and/or photonic mechanism is a natural biological protein or other molecule. Akaike et al., Proc. Annual Conf. IEEE in Medicine and Biology, Part 4/6:1337-1338 (1989). There are presently no examples of a totally synthetic programmable self-assembling molecule which produces an efficient electronic or photonic structure, mechanism or device.
Progress in understanding self-assembly in biological systems is relevant to nanotechnology. Drexler, Proc. Natl. Acad. Sci USA, 78:5275-5278 (1981), and Drexler, xe2x80x9cEngines of Creation,xe2x80x9d Doubleday Publishing Co., New York, N.Y. (1986). Areas of significant progress include the organization of the light harvesting photosynthetic systems, the energy transducing electron transport systems, the visual process, nerve conduction and the structure and function of the protein components which make up these systems. The so called bio-chips described the use of synthetically or biologically modified proteins to construct molecular electronic devices. Haddon et al., Proc. Natl. Acad. Sci. USA, 82:1874-1878 (1985), McAlear et al., xe2x80x9cMolecular Electronic Devices II,xe2x80x9d Carter ed., Marcel Dekker, Inc., New York N.Y., pp. 623-633 (1987).
Some work on synthetic proteins (polypeptides) has been carried out with the objective of developing conducting networks. McAlear et al., xe2x80x9cMolecular Electronic Devices,xe2x80x9d Carter ed., Marcel Dekker, New York, N.Y., pp. 175-180 (1982). Other workers have speculated that nucleic acid based bio-chips may be more promising. Robinson et al., xe2x80x9cThe Design of a Biochip: a Self-Assembling Molecular-Scale Memory Device,xe2x80x9d Protein Engineering, 1:295-300 (1987).
Great strides have also been made in the understanding of the structure and function of the nucleic acids, deoxyribonucleic acid or DNA, Watson, et al., in xe2x80x9cMolecular Biology of the Gene,xe2x80x9d Vol. 1, Benjamin Publishing Co., Menlo Park, Calif. (1987), which is the carrier of genetic information in all living organisms (See FIG. 1). In DNA, information is encoded in the linear sequence of nucleotides by their base units adenine, guanine, cytosine, and thymidine (A, G, C, and T). Single strands of DNA (or polynucleotide) have the unique property of recognizing and binding, by hybridization, to their complementary sequence to form a double stranded nucleic acid duplex structure. This is possible because of the inherent base-pairing properties of the nucleic acids: A recognizes T, and G recognizes C. This property leads to a very high degree of specificity since any given polynucleotide sequence will hybridize only to its exact complementary sequence.
In addition to the molecular biology of nucleic acids, great progress has also been made in the area of the chemical synthesis of nucleic acids. This technology has developed so automated instruments can now efficiently synthesize sequences over 100 nucleotides in length, at synthesis rates of 15 nucleotides per hour. Also, many techniques have been developed for the modification of nucleic acids with functional groups, including: fluorophores, chromophores, affinity labels, metal chelates, chemically reactive groups and enzymes. Smith et al., Nature, 321:674-679 (1986); Agarawal et al., Nucleic Acids Research, 14:6227-6245 (1986); Chu et al., Nucleic Acids Research, 16:3671-3691 (1988).
An impetus for developing both the synthesis and modification of nucleic acids has been the potential for their use in clinical diagnostic assays, an area also referred to as DNA probe diagnostics. Simple photonic mechanisms have been incorporated into modified oligonucleotides in an effort to impart sensitive fluorescent detection properties into the DNA probe diagnostic assay systems. This approach involved fluorophore and chemilluminescent-labeled oligonucleotides which carry out Fxc3x6rster nonradiative energy transfer. Heller et al., xe2x80x9cRapid Detection and Identification of Infectious Agents,xe2x80x9d Kingsbury et al., eds., Academic Press, New York, N.Y. pp. 345-356 (1985). Fxc3x6rster nonradiative energy transfer is a process by which a fluorescent donor group excited at one wavelength transfers its absorbed energy by a resonant dipole coupling process to a suitable fluorescent acceptor group. The efficiency of energy transfer between a suitable donor and acceptor group has a 1/r6 distance dependency (see Lakowicz et al., xe2x80x9cPrinciples of Fluorescent Spectroscopy,xe2x80x9d Plenum Press, New York, N.Y., Chap. 10, pp. 305-337 (1983)). 
As to photonic devices, they can generally be fabricated in dense arrays using well developed micro-fabrication techniques. However, they can only be integrated over small areas limited by the relatively high defect densities of the substrates employed. In order to be useful and economically viable, these devices must in many cases, be used within large area silicon integrated circuits. A good example of this issue is the vertical cavity surface emitting lasers. To address many potential applications, it would be highly desirable to integrate these devices with large area silicon IC""s. A major obstacle in the integration of these new devices with silicon is the existence of material and geometrical incompatibilities. These devices need to be integrated on silicon in large sparse arrays with minimal performance degradation, and without affecting the underlying silicon circuits. Over the past years, a number of component assembly technologies have been extensively investigated regarding the integration of such compound semiconductor devices on silicon. These include hybrid flip-chip bonding or epitaxial lift-off and other direct bonding methods. Although these hybrid technologies have made significant progress and several component demonstrations have shown the viability of these techniques, these methods do not address the problem of geometrical incompatibility. That is, the dimensions with which the specialty devices are fabricated on their mother substrate must be conserved when they are coupled onto the host substrate. This makes the integration of small area devices on large area components economically unfeasible.
A major obstacle in the integration of these new devices with silicon is the existence of material and geometrical incompatibilities. These devices need to be integrated on silicon in large sparse arrays with minimal performance degradation, and without affecting the underlying silicon circuits. Over the past years, a number of component assembly technologies have been extensively investigated regarding the integration of such compound semiconductor devices on silicon. These include hybrid flip-chip bonding or epitaxial lift-off and other direct bonding methods. Although these hybrid technologies have made significant progress and several component demonstrations have shown the viability of these techniques, these methods do not address the problem of geometrical incompatibility. That is, the dimensions with which the specialty devices are fabricated on their mother substrate must be conserved when they are coupled or grafted onto the silicon board.
The prior art has no integration technique that is capable of creating a sparse array of devices distributed over a large area, when the devices are originally fabricated densely over small areas. This makes large area components made up from integration of micron size devices economically unfeasible. To solve this problem, the electronics industry employs a hierarchy of packaging techniques. However, this problem remains unsolved when a regular array of devices is needed on large areas with a relatively small pitch. This problem is probably most noticeable through the high cost associated with the implementation of matrix addressed displays, where the silicon active matrix consists of small transistors that need to be distributed over a large area. Thus, prior art microfabrication techniques limit devices to small area components where a dense array of devices are integrated. However, there are a number of important applications that could benefit from specialty devices being integrated more sparsely over large areas.
One possible method for removing the geometrical limitations is the further development of semiconductor substrate materials to the point where their defect densities approaches that of silicon. This is a long and expensive process that requires incremental progress. A second approach is the development of special robots capable of handling micron and sub-micron size devices and able to graft them to appropriate places. This also seems impractical because the grafting process will remain sequential where one device may be grafted after another, requiring impractical processing times. In any case, both of these approaches may be limited to motherboard dimensions on the order of 10 cm.
With regard to memories, data processing engines have been physically and conceptually separated from the memory which stores the data and program commands. As processor speed has increased over time, there has been a continuous press for larger memories and faster access. Recent advances in processor speed have caused system bottlenecks in access to memory. This restriction is critical because delays in obtaining instructions or data may cause significant processor wait time, resulting in loss of valuable processing time.
Various approaches have been taken to solve these concerns. Generally, the solutions include using various types of memory which have different attributes. For example, it is common to use a relatively small amount of fast, and typically expensive, memory directly associated with the processor units, typically called cache memory. Additionally, larger capacity, but generally slower, memory such as DRAM or SRAM is associated with the CPU. This intermediate memory is often large enough for a small number of current applications, but not large enough to hold all system programs and data. Mass storage memory, which is ordinary very large, but relatively inexpensive, is relatively slow. While advances have been continually made in improving the size and speed of all types of memory, and generally reducing the cost per bit of memory, there remains a substantial need especially to serve yet faster processors.
For the last 20 years most mass storage devices have utilized a rotating memory medium. Magnetic media have been used for both xe2x80x9cfloppyxe2x80x9d (flexible) disks or xe2x80x9chardxe2x80x9d disk drives. Information is stored by the presence or absence of magnetization at defined physical locations on the disk. Ordinarily, magnetic media are xe2x80x9cread-writexe2x80x9d memories in that the memory may be both written to and read from by the system. Data is written to or read from the disk by heads placed close to the surface of the disk.
A more recent development in rotating mass storage media are the optical media. Compact disks are read only memory in which the presence or absence of physical deformations in the disk indicates the data. The information is read by use of a focused laser beam, in which the change in reflectance properties from the disk indicate the data states. Also in the optical realm are various optical memories which utilize magnetooptic properties in the writing and reading of data. These disks are both read only, write once read many (xe2x80x9cWORMxe2x80x9d) drives and multiple read-write memories. Generally, optical media have proved to have a larger storage capacity, but higher costs per bit and limited write ability, as compared with magnetic media.
Several proposals have been made for using polymers for electronic based molecular memories. For example, Hopfield, J. J., Onuchic, J. N. and Beratan, D. N., xe2x80x9cA Molecular Shift Registerxe2x80x9d, Science, 241, p. 817, 1988, discloses a polymer based shift register memory which incorporates charge transfer groups. Other workers have proposed an electronic based DNA memory (see Robinson et al, xe2x80x9cThe Design of a Biochip: A Self-Assembling Molecular-Scale Memory Devicexe2x80x9d, Protein Engineering, 1:295-300 (1987). In this case, DNA is used with electron conducting polymers for a molecular memory device. Both concepts for these molecular electronic memories do not provide a viable mechanism for inputting data (write) and for outputting data (read).
Molecular electronic memories have been particularly disappointing in their practical results. While proposals have been made, and minimal existence proofs performed, generally these systems have not been converted to commercial reality. Further, a specific deficiency of the system described above is that a sequential memory is typically substantially slower than a random access memory for use in most systems.
The optical memories described above suffer from the particular problem of requiring use of optical systems which are diffraction limited. This imposes size restrictions upon the minimum size of a data bit, thereby limiting memory density. This is an inherent limit in systems which store a single bit of data at a given physical memory location.
Further, in all optical memory systems described above, the information is stored on a bit-by-bit basis, such that only a single bit of data is obtained by accessing a giving physical location in memory. While word-wide memory access systems do exist, generally they store but a single bit of information at a given location, thereby requiring substantially the same amount of physical memory space whether accessed in a bit manner or word-wide manner.
While systems have generally increased in speed and storage density, and decreased in cost per bit, there remains a clear gap at present between processor speed and system requirements. See generally, xe2x80x9cNew Memory Architectures to Boost Performancexe2x80x9d, Tom R. Halfhill, Byte, July, 1993, pp 86 and 87. Despite the general desirability of memories which are faster, denser and cheaper per bit, and the specific critical need for mass memory which can meet the demands of modern day processor systems speed, no completely satisfactory solution has been advanced heretofore. The fundamental limitations on the currently existing paradigms cannot be overcome by evolutionary enhancements in those systems.
Despite the clear desirability for new and improved apparatus and methods in this field, no optimal solution has been proposed previously.
Increasingly, the technologies of communication, information processing, and data storage are beginning to depend upon highly-integrated arrays of small, fast electronic and photonic devices. As device sizes scale down and array sizes increase, conventional integration techniques become increasingly costly. The dimensions of photonic and electronic devices permit the use of molecular biological engineering for the integration and manufacturing of photonic and electronic array components. This invention relates to methodologies and manufacturing techniques which utilize programmable functionalized self-assembling nucleic acids, nucleic acid modified structures, and other selective affinity or binding moieties as building blocks for: (1) creating molecular electronic and photonic mechanisms; (2) for the organization, assembly, and interconnection of nanostructures, submicron and micron sized components onto silicon or other materials; (3) for the organization, assembly, and interconnection of nanostructures, submicron and micron sized components within perimeters of microelectronic or optoelectronic components and devices; (4) for creating, arraying, and manufacturing photonic and electronic structures, devices, and systems; (5) for the development of a high bit density (large byte) three and four dimensional optical data storage materials and devices; and (6) for development of low density optical memory for applications in authentication, anti-counterfeiting, and encryption of information in documents or goods. This invention also relates to associated microelectronic and optoelectronic devices, systems, and manufacturing platforms which provide electric field transport and selective addressing of self-assembling, nanostructures, sub-micron and micron size components to selected locations on the device itself or onto other substrate materials.
Functionalized nucleic acids based polymers (e.g., DNA, RNA, peptide nucleic acids, methyphosphonates) constitute a vehicle to assemble large numbers of photonic and electronic devices and systems, utilizing the base-pair coding property of the DNA which allows specific complementary double stranded DNA structures to be formed. This unique property of DNA provides a programmable recognition code (via the DNA sequence) which can be used for specific placement and alignment of nanostructures.
In the preferred embodiment, the process by which photonic devices would be aligned, involves first coating them with a specific DNA sequence. The area of the host substrate where attachment of the devices is desired are coated with the specific complementary DNA sequence. The substrate and DNA-covered devices are released into a solution and hybridization between complementary DNA strands occurs. Hybridization effectively grafts the devices to their proper receptor locations on the substrate.
More broadly, the invention in this respect relates to a method for the fabrication of micro scale and nanoscale devices comprising the steps of: fabricating first component devices on a first support, releasing at least one first component device from the first support, transporting the first component device to a second support, and attaching the first component device to the second support.
Some potential applications for these techniques are: (1) fabricating light emitter arrays over large surfaces; (2) assembly of two or three-dimensional photonic crystal structures; and (3) manufacturing of various hybrid-integrated components including flat panel displays, medical diagnostic equipment and data storage systems.
As photonics plays an increasingly important role in information processing, communication and storage systems it will deliver faster, smaller, more power efficient, and functionally versatile integrated systems at lower cost. New fabrication technologies including nanostructure fabrication, integration and self-assembly techniques are used. As device dimensions shrink to submicron levels, it becomes important to utilize the inventive concepts employing molecular biological engineering concepts and principles as manufacturing techniques for the fabrication of integrated photonic and electronic devices.
These inventions relate to nanostructures, submicron and micron-sized structures incorporating synthetic DNA polymers. This includes DNA modified with small chromophore molecules, to large structures (e.g., micron-sized) which are modified with DNA sequences. Synthetic DNA polymers can be designed with highly specific binding affinities. When covalently attached to nanoscale organic and metallic structures or micron scale semiconductor component devices, DNA polymers can provide a self-assembly fabrication mechanism. This mechanism can be used for both the selective grafting of the devices to specific pre-programmed locations on a desired surface, and for the clustering of devices into pre-programmed 2-D or 3-D lattices. For grafting of photonic or electronic component devices onto host substrates, DNA polymers with complementary sequences are first synthesized. The photonic component devices and desired areas of the host substrate (receptor areas) are coated with the complementary DNA sequences. The host substrates are then introduced into a solution.
In one aspect of this invention, a method for fabrication of nanoscale and microscale structures is provided comprising the steps of: providing a structure with multiple affinity surface identities, orienting the structure in an electric field, and reacting the oriented structure with an affinity site.
In yet another aspect of this invention, a method for forming a multiple identity substrate material is provided comprising the steps of: providing a first affinity sequence at multiple locations on a support, providing a functionalized second affinity sequence, which reacts with the first affinity sequence, and has an unhybridized overhang sequence, and selectively cross-linking first affinity sequences and second affinity sequences.
In yet another aspect of this invention, a method for the assembly of chromophoric structures is provided comprising the steps of: selectively irradiating a photoactivatable region, whereby an electric field is generated corresponding to the region, providing charged reactants in solution which includes the electric field, and repeating the selective irradiation to sequentially assemble the chromophoric structures.
It is an object of this invention to enable nanotechnology and self-assembly technology by the development of programmable self-assembling molecular construction units.